Cytokines synthase expression

D16. De Vera, M. E Kim, Y. M., Wong, H. R Wang, Q Billiar, T. R., and Geller, D. A., Heat shock response inhibits cytokine-inducible nitric oxide synthase expression in rat hepatocytes. Hepatology 24,1238-1245 (1996). 

Red wine contains quercetin, rutin, catechin, and epicatechin, among other flavonoids (Frankel and others 1993). Quercetin and other phenolic compounds isolated from wines were found to be more effective than a-tocopherol in inhibiting copper-catalyzed LDL oxidation. It has been determined that quercetin has also several anti-inflammatory effects it inhibits inflammatory cytokine production (Boots and others 2008), inducible NO synthase expression and activation of inflammatory transcription factors (Hamalainen and others 2007), and activity of cyclooxygenase and lipooxygenase (Issa 2006), among others. 

Geng, Y. J., Petersson, A. S., Wennmalm, A., and Hansson, G. K. (1994). Cytokine-induced expression of nitric oxide synthase results in nitrosylation of heme and nonheme iron proteins in vascular smooth muscle cells. Exp. Cell Res. 214, 418-428. 

Isolated cells from infected mice are less proliferative upon in-vitro activation and increase inducible nitric oxide synthase expression in peritoneal cells, yet splenocytes have normal cytokine responses to ConA (Dai and Gottstein, 1999)... 

Maggi, L. B.Jr., Sadeghi, H., Weigand, C., Scarim, A. L., Heitmeier, M. R., and Corbett, J. A. (2000). Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone Evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. Diabetes 49, 346-355. 

Dlaska, M. and Weiss, G. 1999. Central role of transcription factor NF-IL6 for cytokine and iron-mediated regulation of murine inducible nitric oxide synthase expression. J Immunol 162 6171-6177. 

The other broad category of MSP actions on macrophages relates to mediator production. Endotoxin, or combinations of proinflammatory cytokines, causes expression of murine macrophage-inducible nitric oxide synthase, an effect that can be detected by Northern blots for the mRNA or by measurement of nitrate in the culture fluid. MSP prevents induction of NO-synthase by any of the above stimuli (Wang et al., 1994d). The inhibitory action of MSP is confined to this specific mediator. MSP did not inhibit endotoxin-induced expression of mRNA for monocyte chemoattractant protein-1. Furthermore, MSP caused secretion of IL-6 (but not IL-1 or TNFa) within 6 hr, and did not inhibit endotoxin-induced secretion of IL-1, IL-6, or TNFa (A. Skeel and E. J. Leonard, unpublished data). The in vitro modulation by MSP of endotoxin-induced NO production now has an in vivo counterpart. Concentrations of nitrate in serum of Stk / mice that received endotoxin intravenously were higher than in serum of comparably treated normal mice and at a critical endotoxin dose, only 20% of the Stk / mice survived, compared to 80% survival for normal mice (Correll et al., 1997). If MSP plays a role in the host response to endotoxemia, pro-MSP must be cleaved to biologically active MSP. Within 4 hr after i.v. administration of... 

Markewitz, B. A., Michael, J. R., and Kohan, D. E. (1993). Cytokine-induced expression of a nitric oxide synthase in rat renal tubule cells. J. Clin. Invest. 91, 2138-2143. 

TakahasU M, Takahashi S, Shimpo M, et al. beta-veiy low density lipoprotein enhances indncible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cells. Atherosclerosis 2002 162 307-313. 

Chester, D.A., McCutcheon, J.A., and Reiss, C.S. (2004). Posttransciiptional Regulation of Neuronal Nitric Oxide Synthase Expression by IFN-gamma. J. Interferon. Cytokine Res. 24, 141-149. 

Inducible NO synthase (iNOS) is usually not constitutively expressed, but can be induced in macrophages by bacterial lipopolysaccharide (LPS), cytokines and other-agents. Although primarily identified in macrophages, expression of the enzyme can be stimulated in virtually any cell or tissue, provided the appropriate inducing agents have been identified (for review see [1] and [3]). 

Exposure to trichothecenes at levels that partially inhibit translation upregulates expression of many inflammatory and immune-related genes including macrophage, Thl and Th2 cytokines as well as chemokines, cyclooxygenase 2 and inducible nitric oxide synthase.1518 Contrastingly, suppressive effects of trichothecenes on leukocyte function are intimately linked with the induction of apoptosis as has been demonstrated in macrophages, T cells and B cells both in vivo and in vitro.19-20... 

To set up and validate the in vitro systems we initiated a study with rat Uver slices. Stimulation by Upopolysaccharide (LPS) in liver slices was used to evoke a pro-inflammatory response in the Uver. Lipopolysaccharide (LPS), a component of Gram-negative bacterial ceU walls (also called endotoxin), has been associated with tissue injury and sepsis. In the Uver LPS activates the resident macrophages, the Kupffer ceUs, which results in cytokine release [96]. Furthermore, LPS is cleared by the Uver, mainly by Kupffer ceUs [97]. One of the major features of endotoxic shock is the induction of nitric oxide S5mthase in the Uver [98]. Inducible nitric oxide synthase (iNOS), the expression of which is induced by LPS and cytokines, produces nitric oxide (NO) in large quantities [99]. 

As in other tissues, glucocorticoids inhibit production of inflammatory cytokines (TNF-ct, IL-1) and chemokines (IL-8) reduce expression of inflammatory cell adhesion molecules and inhibit gene transcription of nitric oxide synthase, phospholipase A2, cydooxygenase-2, and NF- . 

Posadas, I., Terencio, M. C, Giannini, C, D Auria, M. V., and Paya, M. (2001). Dysidotronic acid, a new sesquiterpenoid, inhibits cytokine production and the expression of nitric oxide synthase. Eur. J. Pharmacol. 415, 285-292. 

DOM treatment also rapidly decreases cellular GSH, which precedes neurotoxicity. This decrease is primarily due to DOM-mediated GSH efflux. DOM also induces an increase in oxidative stress as indicated by increases in ROS and lipid peroxidation products, which follow GSH efflux. Astrocytes from both genotypes are resistant to DOM-mediated neurotoxicity and present a diminished Ca2+ response to DOM-mediated toxicity (Walser et al., 2006). Exposure of neonatal rat microglia to DOM triggers the release of TNF-a and matrix metalloproteinase-9 (MMP-9) (Mayer et al., 2001). These molecules are involved in the modulation of neuroinflammation in brain (Farooqui et al., 2007). Collective evidence suggests that DOM-mediated neurodegeneration involves changes in cellular redox, oxidative stress, and increased expression of cytokines, nitric oxide synthase, NADPH diaphorase, and matrix metalloproteinase-9 (Walser et al., 2006 Chandrasekaran et al., 2004 Ananth et al., 2003a,b Mayer et al., 2001). 

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